Introduction. The Mars500 project was aimed to simulate a flight to Mars to prepare for future deep-space exploration. It lasted 520 days, from Jun 3rd 2010 to Nov 4th 2011. The experimental facility was located in the Institute of Biomedical Problems (IBMP) of the Russian Academy of Science (RSA), Moscow. The Mars500 six crew-members (three Russians, two Europeans, and one Chinese, aged 32.4±4.8 years) lived in this spaceship-like habitat with continuous temporal and spatial isolation, realistic mission activities, a diurnal weekly work schedule, communication lag, a mid-mission landing on a simulated Mars surface and other major special conditions of a Martian flight (http://mars500.imbp.ru/en/index_e.html). Aim. To evaluate the effect of long-term confinement on (i) weight and body mass index (BMI); (ii) fasting plasma glucose (FPG), insulin and Homeostatic Model Assessment (HOMA) index; (iii) hormonal status related to food-intake (ghrelin) and adipose tissue (leptin and adiponectin) and (iv) total cholesterol (TC); high-density lipoprotein (HDL)-C, low-density-lipoprotein (LDL)-C and triglyceride (TG). Results. All six crew members carried out the Mars-520 program in full, did not show any major clinically appreciable pathological change. Wilcoxon matched-pairs signed rank test between pre (-7 d; BDC) and post (518-d) data sampling showed significant median changes only for BMI (-2.1 kg/m2, p=0.03), FPG (+22.1 mg/dL, p=0.03) and ghrelin (+64.9 pg/mL, p=0.03). To further investigate the effect of long-confinement over the entire course of isolation, we performed a non-parametric Friedman test on the above reported parameters. Median changes for weight and BMI began to decrease after about the half of the experiment and reached a significant difference at the end of the isolation itself (-6%, p<0.01, for both). FPG did not vary over the first 168-d, but progressively increased afterwards, reaching a plateau starting from 417-d (+ 29%, p<0.001) till the end of the experiment (511-d, +19% and 518-d, +22%; for both p<0.05). Insulin showed an early increment (60-d; +87%) which was steadily maintained up to 518-d (+138%). A same trend was recorded for HOMA-index. Plasma C-peptide levels did not change appreciably over the entire isolation, whereas insulin/C-peptide ratio progressively increased in parallel with insulin concentrations. Notably, FPG and insulin/C-peptide ratio both peaked at 417-d. Plasma adiponectin and its related HMW form dropped after 60-d being halved (-51% p<0.05), remained at this nadir level for further 60-d and then progressively returned to baseline levels towards the end of isolation. Sixty-d after the hatch closure, plasma leptin doubled, whereas no changes were shown at the others time points. Consequently, the leptin/adiponectin ratio tripled at 60-d and progressively decreased to about baseline values at 518-d. The gut hormone ghrelin resulted in an early increment (60-d, +23%) reaching a plateau at 417-d (+77% vs. BDC), which was maintained up to 512 mission days (+96% vs. BDC, p<0.05). Conclusions. The data obtained with the Mars-500 experiment suggest that environmental stress has a strong impact on glucose metabolism upon through the involvement of adipose tissue (adiponectin secretion). This indicates the need for both further studies in this field, future mission simulations or real space flights, and the implementation of specific countermeasures, including nutritional and nutraceutical approaches, and improved exercise patterns.